Post-Operative Functional Outcomes in Early Age Onset Rectal Cancer

Background: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (<50 years) is rising, there is little data on functional outcomes in this group. Methods: The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, <50 years of age at time of diagnosis and with documented follow-up including functional outcomes. Results: A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). Conclusion: A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters

Management of Lateral Lymph Node Metastasis in Rectal Cancer

Introduction: Pre-treatment abnormal lateral lymph nodes (LLNs) are present in approximately 20% of patients with locally advanced rectal cancer. Western treatment of LLNs consists of neoadjuvant (chemo)radiotherapy (nCRT) followed by total mesorectal excision (TME), meaning these nodes are not removed surgically. There is, however, potential benefit in performing an additional lateral lymph node dissection (LLND) as enlarged LLNs have been shown to be predictive for local recurrence. Furthermore, the impact on oncological outcomes when enlarged LLNs harbour malignant features is currently unknown. Therefore, the aims of this thesis were to investigate if patients benefit from an additional LLND after nCRT and to determine oncological outcomes when malignant features are present in enlarged LLNs. Methods: A multi-centre cohort study was conducted at six tertiary referral centres in the US, the Netherlands and Australia. All patients had locally advanced rectal cancer with enlarged LLNs with a short-axis of ≥5mm. Malignant features were defined as nodes with internal heterogeneity and/or border irregularity. Firstly, patients who underwent nCRT followed by TME (LLND-) were compared to those who underwent a LLND in addition to nCRT and TME (LLND+). Next, a systematic review and meta-analysis was performed on studies comparing LLND- versus LLND+. Finally, patients with and without malignant features were compared. Outcomes of interest were local recurrence-free survival (LRFS), distant metastatic-free survival (DMFS), disease-free survival (DFS), and overall survival (OS). Results: LLND+ patients (n=44) were younger with higher ASA-classifications and ypN-stages compared to LLND- patients (n=115). LLND+ patients had larger median LLNs short-axes and received more adjuvant chemotherapy (100 vs. 30%; p<0.0001). Between groups, LRFS was 97% for LLND+ versus 89% for LLND- (p=0.13). DFS (p=0.94) and OS (p=0.42) were similar. LLND was an independent significant factor for local recurrences (p=0.01) in the multi-variate analysis. Sub-analysis of patients who underwent long-course nCRT and had adjuvant chemotherapy (LLND- n=30, LLND+ n=44) demonstrated a higher LRFS for LLND+ patients (97% versus 84% for LLND-; p=0.04). DFS (p=0.10) and OS (p=0.11) were similar between groups. Seven studies were included in the systematic review. Five-year LRFS after LLND+ was improved (range 85-95%) compared to LLND- (43-89%; statistically significant in three studies). DFS was increased after LLND+ (range 61-74%) compared to LLND- (54-79%; significant in three studies). No study reported five-year overall survival benefit after LLND+ (range 72-80%; 69-91% for LLND-). In the analysis of malignant features, median LLNs short-axis was 7mm (range 5-28) for the complete cohort, of whom 60 patients (52%) had malignant features. LLNs with malignant features showed no difference in LRFS (p=0.20) but had worse DMFS (p=0.004) and OS (p=0.006) compared to those without malignant features. Cox regression analysis confirmed malignant features as an independent factor for DMFS. Conclusions: This thesis suggests that a LLND in addition to nCRT in locally advanced rectal cancer improves LRFS and DFS, and that malignant features present in enlarged LLNs are predictive for a worse DMFS. More high-quality studies are required to further explore the value of LLND and the role of malignant features in LLNs.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 202

A Propensity Score Matched Analysis of Open Versus Minimally Invasive Transthoracic Esophagectomy in the Netherlands

Objective: The aim of this study was to compare open esophagectomy (OE) with minimally invasive esophagectomy (MIE) in a population-based setting.  Background: Randomized controlled trials and cohort studies have shown that MIE is associated with reduced pulmonary complications and shorter hospital stay as compared to OE.  Methods: Patients who underwent transthoracic esophagectomy for cancer between 2011 and 2015 were selected from the national Dutch Upper Gastrointestinal Cancer Audit. Hybrid, transhiatal, and emergency procedures were excluded. Patients who underwent OE were compared with those treated by MIE. Propensity score matching was used to correct for differences in baseline characteristics. The primary endpoint was postoperative pulmonary complications; secondary endpoints were morbidity, mortality, convalescence, and pathology.  Results: Some 1727 patients were included. After propensity score matching the percentage of patients with 1 or more complications was 62.6% after OE (N = 433) and 60.2% after MIE (N = 433) (P = 0.468). Pulmonary complication rate did not differ between groups: 34.2% (OE) versus 35.6% (MIE) (P = 0.669). Anastomotic leak (15.5% vs 21.2%, P = 0.028) and reintervention rates (21.1% vs 28.2%, P = 0.017) were higher after MIE. Mortality was 3.0% in the OE group and 4.7% in the MIE group (P = 0.209). Median hospital stay was shorter after MIE (14 vs 13 days, P = 0.001). Percentages of R0 resections (93%) did not differ between groups. The median (range) lymph node count was 18 (2-53) (OE) versus 20 (2-52) (MIE) (P < 0.001).  Conclusions: This population-based study showed that mortality and pulmonary complications were similar for OE and MIE. Anastomotic leaks and reinterventions were more frequently observed after MIE. MIE was associated with a shorter hospital stay

Impact of microsatellite status in early-onset colonic cancer

Background: The molecular profile of early-onset colonic cancer is undefined. This study evaluated clinicopathological features and oncological outcomes of young patients with colonic cancer according to microsatellite status. Methods: Anonymized data from an international collaboration were analysed. Criteria for inclusion were patients younger than 50 years diagnosed with stage I-III colonic cancer that was surgically resected. Clinicopathological features, microsatellite status, and disease-specific outcomes were evaluated. Results: A total of 650 patients fulfilled the criteria for inclusion. Microsatellite instability (MSI) was identified in 170 (26.2 per cent), whereas 480 had microsatellite-stable (MSS) tumours (relative risk of MSI 2.5 compared with older patients). MSI was associated with a family history of colorectal cancer and lesions in the proximal colon. The proportions with pathological node-positive disease (45.9 versus 45.6 per cent; P = 1.000) and tumour budding (20.3 versus 20.5 per cent; P = 1.000) were similar in the two groups. Patients with MSI tumours were more likely to have BRAF (22.5 versus 6.9 per cent; P < 0.001) and KRAS (40.0 versus 24.2 per cent; P = 0.006) mutations, and a hereditary cancer syndrome (30.0 versus 5.0 per cent; P < 0.001; relative risk 6). Five-year disease-free survival rates in the MSI group were 95.0, 92.0, and 80.0 per cent for patients with stage I, II, and III tumours, compared with 88.0, 88.0, and 65.0 per cent in the MSS group (P = 0.753, P = 0.487, and P = 0.105 respectively). Conclusion: Patients with early-onset colonic cancer have a high risk of MSI and defined genetic conditions. Those with MSI tumours have more adverse pathology (budding, KRAS/BRAF mutations, and nodal metastases) than older patients with MSI cancers